Diaminotrifluoromethylpyridine derivatives and phospholipase A2 inhibitor containing them

ABSTRACT

A diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR1## wherein X is --CW 1  R 1 , --COCOR 2 , --CW 1  NHCOR 2 , --C(═W 1  (W 2  W 3  or --CW 1  N(R 4 )R 5 , and Y is alkyl, --CW 3  R 6 , --COCOR 7 , --NHCOR 7 , --C(═W 3 )W 4  R 8 , --(NH) m  SO 2  R 9 , --(NH) m  SO 2  OR 10  or --(NH) m  SO 2  N R 11 )R 12 , wherein each of R 1 , R 6  and R 9 , which are independent from one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted, each of R 2  and R 7 , which are independent from each other, is alkyl which may be substituted, alkoxy which may be substituted, phenyl which may be substituted or phenoxy which may be substituted, each of R 3 , R 8   and R 10 , which are independent from one another, is alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted or benzyl which may be substituted, each of R 4 , R 5 , R 11  and R 12 , which are independent from one another, is alkyl which may be substituted, each of W 1 , W 2 , W 3  and W 4 , which are independent from one another, is an oxygen atom or a sulfur atom, and m is 0 or 1, provided that a combination wherein one of X and Y is --COCF 2  X 1  wherein X 1  is a hydrogen atom, a halogen atom, alkyl or haloalkyl, and the other is --COCF 2  X 2  wherein X 2  is a hydrogen atom, a halogen atom, alkyl, haloalkyl or alkylcarbonyl, or --COOX 3  wherein X 3  is alkyl which may be substituted or phenyl which may be substituted, is excluded.

The present invention relates to novel diaminotrifluoromethylpyridine derivatives or their salts, a process for their production, a phospholipase A₂ inhibitor, an anti-inflammatory agent and an anti-pancreatitis agent containing them, and novel trifluoromethylpyridine derivatives as intermediates.

As a diaminotrifluoromethylpyridine derivative, for example, U.S. Pat. Nos. 3,746,531 and 3,962,263 disclose a pyridine as an active ingredient of a herbicide, which has trifluoromethyl at the 5-position, --NHCO--CF₂ --T¹ wherein T¹ is a hydrogen atom, a chlorine atom, a fluorine atom, alkyl or haloalkyl at either the 2-position or the 3-position, and --NHCO--CF₂ -T² wherein T² is a hydrogen atom, a chlorine atom, a fluorine atom, alkyl, haloalkyl or alkylcarbonyl, or --NHCOOT³ wherein T³ is C₁₋₄ lower alkyl or phenyl at the other position. However, this is different in the chemical structure from the diaminotrifluoromethylpyridine derivative of the present invention. Further, U.S. Pat. No. 3,961,063 discloses a trifluoromethyl-substituted pyridine as an active ingredient of an anthelmintic, which has --NHCSNHCOT⁴ wherein T⁴ is alkoxy, at the 2- and 3-positions. However, this compound is different in the chemical structure from the diaminotrifluoromethylpyridine derivative of the present invention.

The present invention provides a diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR2## wherein X is --CW¹ R¹, --COCOR², --CW¹ NHCOR², --C(═W¹)W² R³ or --CW¹ N(R⁴)R⁵, and Y is alkyl, --CW³ R⁶, --COCOR⁷, --NHCOR⁷, --C(═W³)W⁴ R⁸, --(NH)_(m) SO₂ R⁹, --(NH)_(m) SO₂ OR¹⁰ or --(NH)_(m) SO₂ N(R¹¹)R¹², wherein each of R¹, R⁶ and R⁹, which are independent from one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted, each of R² and R⁷, which are independent from each other, is alkyl which may be substituted, alkoxy which may be substituted, phenyl which may be substituted or phenoxy which may be substituted, each of R³, R⁸ and R¹⁰, which are independent from one another, is alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted or benzyl which may be substituted, each of R⁴, R⁵, R¹¹ and R¹², which are independent from one another, is alkyl which may be substituted, each of W¹, W², W³ and W⁴, which are independent from one another, is an oxygen atom or a sulfur atom, and m is 0 or 1, provided that a combination wherein one of X and Y is --COCF₂ X¹ wherein X¹ is a hydrogen atom, a halogen atom, alkyl or haloalkyl, and the other is --COCF₂ X² wherein X² is a hydrogen atom, a halogen atom, alkyl, haloalkyl or alkylcarbonyl, or --COOX³ wherein X.sup. 3 is alkyl which may be substituted or phenyl which may be substituted, is excluded; a process for its production; a phospholipase A₂ inhibitor, an anti-inflammatory agent and an anti-pancreatitis agent containing it, and a trifluoromethylpyridine derivative as an intermediate.

Now, the present invention will be described in detail with reference to the preferred embodiments.

In the formula (I), the chain hydrocarbon group for each of R¹, R⁶ and R⁹ may be alkyl, alkenyl or alkynyl. The monocyclic hydrocarbon group may be cycloalkyl, cycloalkenyl or phenyl. The polycyclic hydrocarbon group may be a condensed polycyclic hydrocarbon group such as naphthyl, tetrahydronaphthyl or indanyl, or a bridged polycyclic hydrocarbon group such as adamantyl, noradamantyl, norbornanyl or norbornanonyl. The monocyclic heterocycle group may be pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxopyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl or morphorinyl. The polycyclic heterocycle group may be a condensed polycyclic heterocycle group such as thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl or quinoxalinyl, or a bridged polycyclic heterocycle group such as quinuclidinyl.

The substituent for each of the chain hydrocarbon group which may be substituted for each of R¹, R⁶ and R⁹, the alkyl which may be substituted and the alkoxy which may be substituted for each of R² and R⁷, the alkyl which may be substituted, the alkenyl which may be substituted and the alkynyl which may be substituted for each of R³, R⁸ and R¹⁰, the alkyl which may be substituted for each of R⁴, R⁵, R¹¹ and R¹² and the alkyl which may be substituted for X³, may be a halogen atom, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino or alkyl-substituted amino. The number of such substituents or substituents on such substituents may be one or more. When the number is two or more, such substituents may be the same or different.

The substituent for each of the monocyclic hydrocarbon group which may be substituted, the polycyclic hydrocarbon group which may be substituted, the monocyclic heterocycle group which may be substituted and the polycyclic heterocycle group which may be substituted for each of R¹, R⁶ and R⁹, the phenyl which may be substituted and the phenoxy which may be substituted for each of R² and R⁷, the cycloalkyl which may be substituted, the phenyl which may be substituted and the benzyl which may be substituted for each of R³, R⁸ and R¹⁰, and the phenyl which may be substituted for X³, may be a halogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkyl-substituted amino, cyano or nitro. The number of such substituents or substituents for such substituents may be one or more. If the number is two or more, such substituents may be the same or different.

In the formula (I), the alkyl group and the alkyl moiety contained in each of X and Y may be C₁₋₁₈ alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl group and the alkenyl moiety contained in each of X and Y may be C₂₋₁₈ alkenyl such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl or nonadecenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group and the alkynyl moiety contained in each of X and Y may be C₂₋₁₈ alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, decynyl or nonadecynyl, and they include linear or branched aliphatic structural isomers. The cycloalkyl group and the cycloalkyl moiety contained in each of X and Y may be C₃₋₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. The cycloalkenyl group and the cycloalkenyl moiety contained in each of X and Y may be C₅₋₈ cycloalkenyl such as cyclopentenyl, cyclohexenyl or cyclooctenyl. The halogen atom contained in each of X and Y may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The aryl group and the aryl moiety contained in each of X and Y may be phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl.

Now, preferred embodiments of the compound of the present invention will be described. In the formula (I), it is preferred that X is --CW¹ R¹ or --C(═W¹)W² R³, and Y is --SO₂ R⁹. Each of R¹ and R⁶ is preferably alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted, phenyl which may be substituted, tetrahydronaphthyl which may be substituted, indanyl which may be substituted or thienyl which may be substituted, more preferably, alkyl, haloalkyl, alkenyl, haloalkenyl, cycloalkyl, halogen-substituted cycloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl. Each of R² and R⁷ is preferably alkoxy which may be substituted or phenyl which may be substituted, more preferably alkoxy, haloalkoxy, phenyl, or halogen-substituted phenyl. Each of R³, R⁸ and R¹⁰ is preferably alkyl which may be substituted, more preferably, alkyl or haloalkyl. Each of R⁴, R⁵, R¹¹ and R¹² is preferably alkyl. R⁹ is preferably alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, cycloalkenyl which may be substituted or phenyl which may be substituted, more preferably alkyl, haloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl.

Preferred specific compounds of the present invention include N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyacetamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene)carboxamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-(2-thienyl)acrylamide, and their salts.

The compound of the formula (I) may form a salt when Y is --SO₂ R⁹ wherein R⁹ is as defined above. Such a salt may be any pharmaceutically acceptable salt, for example, an alkali metal salt such as a potassium salt or a sodium salt, an alkaline earth metal salt such as a calcium salt, or an organic amine salt such as a triethanol amine salt or a tris(hydroxymethyl)aminomethane salt. Such a salt may have crystal water.

The compounds of the formula (I) and (I-1) can be prepared, for example, by processes represented by the following reactions (A) and (B): ##STR3##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X and Y are as defined above, and Z is a halogen atom. ##STR4##

In the above formulas, Y¹ is --CW³ R⁶, --COCOR⁷ or --C(═W³)W⁴ R⁸, wherein R⁶, R⁷, R⁸, W³, W⁴, X and Z are as defined above.

A compound of the formula (I-1) wherein X and Y¹ are the same substituents, can be prepared in the same manner as the Reaction (B) using as the starting material 2,3-diamino-5-trifluoromethylpyridine instead of the compound of the formula (III).

The reactions (A) and (B) are usually conducted in the presence of a solvent, if necessary, by using a base. The solvent may be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a cyclic or non-cyclic aliphatic hydrocarbon such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, trichloroethane, n-hexane or cyclohexane; an ether such as diethyl ether, dioxane or tetrahydrofuran; a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone; a nitrile such as acetonitrile or propionitrile; an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or sulfolane. The base may be an inorganic base or an organic base. The inorganic base may, for example, be an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkali metal or alkaline earth metal carbonate such as anhydrous potassium carbonate or anhydrous calcium carbonate; an alkali metal hydride such as sodium hydride; or an alkali metal such as sodium metal. The organic base may be pyridine or triethylamine.

In the Reactions (A) and (B), a dehydrating condensation agent is required for the reaction with HOOCR¹ or HOOCR⁶. Such a dehydrating condensation agent may be dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction temperature is usually within a range of -30° to +100° C., preferably from 0° to 60° C., and the reaction time is usually within a range of from 1 to 24 hours, preferably from 1 to 10 hours.

The compound of the formula (II) can be prepared, for example, by processes represented by the following Reactions (C), (D) and (E): ##STR5##

In the above formulas, Y is as defined above.

The amination step in the above Reaction (C) is conducted usually in the presence of a solvent, if necessary, by using a base. The solvent may be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a cyclic or non-cyclic aliphatic hydrocarbon such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, trichloroethane, n-hexane or cyclohexane; an ether such as diethyl ether, dioxane or tetrahydrofuran; a nitrile such as acetonitrile or propionitrile; or an aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide or sulfolane. The base may be the same as the one useful for the above-mentioned Reactions (A) and (B). The reaction temperature is usually within a range of from -30° to +100° C., and the reaction time is usually from 1 to 24 hours.

The reduction reaction in the reduction step in the above Reaction (C) may be conducted by a method wherein an acid such as hydrochloric acid or acetic acid is used together with iron or zinc, a method wherein sodium hydrosulfide, potassium hydrosulfide, sodium sulfide, potassium sulfide or sodium hydrosulfite is used, or a method of catalytic hydrogenation wherein hydrogen is used in the presence of a palladium catalyst or a nickel catalyst. The solvent to be used for the reduction may be optionally selected depending upon the reduction method. Usually, an alcohol such as methanol, ethanol or propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran or acetonitrile may be employed. The reaction temperature is usually from 0° to 100° C., and the reaction time is usually from 1 to 24 hours.

(i) In a case where Y is --CW³ R⁶ or --COCOR⁷ ##STR6##

In the above formulas, Y² is --CW³ R⁶ or --COCOR⁷, wherein R⁶, R⁷, W³ and Z are as defined above.

The protecting group addition step and the Y² -modification step in the above Reaction (D) can be conducted in the same manner as in the above Reactions (A) and (B). Further, the protecting group removal step in the above Reaction (D) can be conducted by catalytic hydrogenation by means of a palladium catalyst such as palladium carbon usually in the presence of a solvent or by the hydrolysis usually in the presence of a solvent and an acid or base. The solvent may be water; an alcohol such as methanol or ethanol; or an ether such as diethyl ether, dioxane or tetrahydrofuran. The acid may be hydrobromic acid or trifluoroacetic acid. The base may be lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate. The reaction temperature is usually from 0° to 100° C., and the reaction time is usually from 1 to 24 hours.

(ii) In a case where Y is --SO₂ R⁹ ' ##STR7##

In the above formulas, Y³ is --SO₂ R⁹ ', R⁹ ' is alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted or cycloalkenyl which may be substituted.

The amination step in the above Reaction (E) can be conducted usually in the presence of a solvent by means of a base. The solvent may be an aprotic polar solvent such as dimethyl acetamide, 1,3-dimethyl-2-imidazolidinone or dimethylsulfoxide. The base may be an inorganic base, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as anhydrous potassium carbonate or anhydrous sodium carbonate. The reaction temperature is usually from 80° to 150° C., and the reaction time is usually from 1 to 10 hours.

The sulfonyl-modification step in the above Reaction (E) can be conducted in the same manner as in the above Reactions (A) and (B).

The nitration step in the above Reaction (E) can be conducted by reacting with nitric acid or nitrate usually in the presence of a solvent. The nitrate may be sodium nitrate or potassium nitrate. The solvent may be acetic acid, acetic anhydride or trifluoroacetic acid. The reaction temperature is usually from 50° to 120° C., and the reaction time is usually from 1 to 10 hours.

The reduction step in the above Reaction (E) can be conducted in the same manner as the reduction step in the above Reaction (C).

The compound of the above formula (III) can be prepared, for example, by a process represented by the following Reaction (F). ##STR8##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X and Z are as defined above.

The above Reaction (F) can be conducted in the same manner as the above Reactions (A) and (B).

Among the compounds of the formula (IV), those wherein Y is --SO₂ R⁹, --SO₂ OR¹⁰ or --SO₂ N(R¹¹)R¹², can be produced also by a process represented by the following Reaction (G). ##STR9##

In the above formulas, Y⁴ is --SO₂ R⁹, --SO₂ OR¹⁰ or --SO₂ N(R¹¹)R¹², wherein R⁹, R¹⁰, R¹¹ and R¹² are as defined above.

The above Reaction (G) can be conducted in the same manner as the sulfonyl-modification step in the above Reaction (E).

The compound of the formula (I) can also be prepared by the following alternative method represented by a Reaction (H). ##STR10##

In the above formulas, R¹, R², R³, R⁴, R⁵, W¹, W², X, Y and Z are as defined above.

The X-modification step in the above Reaction (H) can be conducted in the same manner as the above Reaction (A), and the amination step is conducted in the same manner as the amination step in the above Reaction (C).

Among the compounds of the above formulas (II), (IV), (IV-1), (V), (VI) and (VII), the following compounds are novel compounds and can be produced by the above Reactions (C), (E) and (G).

Trifluoromethylpyridine derivatives of the formula (VIII): ##STR11## wherein Q is a hydrogen atom, nitro or amino, and Y⁵ is --(NH)_(m) --SO₂ R⁹ wherein R⁹ and m are as defined above, --(NH)_(m) --SO₂ OR¹⁰ wherein R¹⁰ and m are as defined above, or --(NH)_(m) --SO₂ N(R¹¹)R¹² wherein R¹¹, R¹² and m are as defined above, provided that when Q is a hydrogen atom and m is 0, R⁹ is other than naphthyl or phenyl which may be substituted.

Now, Preparation Examples for the compounds of the present invention will be described.

PREPARATION EXAMPLE 1 Preparation of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)pentafluoropropionamide (Compound No. 19)

(1) 3.1 g of ethanesulfonamide was dissolved in 50 ml of dry tetrahydrofuran, and 1.2 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 5.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and then the mixture was reacted for 7 hours under reflux. After completion of the reaction, the reaction product was poured into 200 ml of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 3.6 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 160° to 163° C.

(2) 1.5 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide obtained in the above step (1) was dissolved in 30 ml of methanol, and 0.2 g of 5% palladium/carbon was added thereto, and a reduction reaction was conducted under a hydrogen pressure overnight under stirring. After completion of the reaction, 5% palladium/carbon was separated by filtration, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane and dried to obtain 1.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 118° to 120° C.

(3) 0.50 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide obtained in the above step (2) was suspended in 10 ml of dry diethyl ether, and 1.15 g of perfluoropropionic anhydride was dropwise added under cooling with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature for one hour. After completion of the reaction, the reaction product was poured into ice water and extracted with ethyl acetate. The extract layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane/ethyl ether to obtain 0.58 g of the desired product (Compound No. 19) having a melting point of from 168° to 170° C.

PREPARATION EXAMPLE 2 Preparation of N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide (Compound No. 10)

(1) 4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.

(2) 4.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide obtained in the above step (1) was dissolved in 66 ml of methanol, and 0.4 g of 5% palladium/carbon was added thereto. A reduction reaction was conducted under a hydrogen pressure overnight under stirring. After completion of the reaction, 5% palladium/carbon was separated by filtration, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane and dried to obtain 3.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 128° to 130° C.

(3) 0.50 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)methanesulfonamide obtained in the above step (2) was dissolved in 6 ml of dry tetrahydrofuran, and 0.37 g of p-fluorobenzoyl chloride was dropwise added under cooling with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the reaction product was poured into ice water and extracted with ethyl acetate. The extract layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue thereby obtained was crystallized from n-hexane/ethyl ether to obtain 0.61 g of the desired product (Compound No. 10) having a melting point of from 211° to 213° C.

PREPARATION EXAMPLE 3 Preparation of N-(3-trichloroacetylamino-5-trifluoromethyl-2-pyridyl)trifluoroacetamide (Compound No. 30)

(1) Into 38 ml of dry tetrahydrofuran, 1.5 g of 2,3-diamino-5-trifluoromethylpyridine was dissolved, and a solution mixture comprising 1.54 g of trichloroacetyl chloride and 3.8 ml of dry tetrahydrofuran was dropwise added thereto over a period of 10 minutes. Then, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, precipitated crystals were collected by filtration and washed with tetrahydrofuran to obtain 2.2 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide having a melting point of from 210° to 223° C.

(2) 2.20 g of N-(2-amino-5-trifluoromethyl-3-pyridyl)trichloroacetamide obtained in the above step (1) was dissolved in 45 ml of dry tetrahydrofuran, and a solvent mixture comprising 2.15 g of trifluoroacetic anhydride and 3 ml of dry tetrahydrofuran was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl ether to obtain 1.20 g of the desired product (Compound No. 30) having a melting point of from 166° to 168° C.

PREPARATION EXAMPLE 4 Preparation of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide (Compound No. 47)

(1) 20.3 g of ethanesulfonamide and 26.0 g of 2-chloro-5-trifluoromethylpyridine were dissolved in 220 ml of dimethylsulfoxide, and 47.4 g of anhydrous potassium carbonate was further added thereto. This solution mixture was heated to 130° C. and reacted for 5 hours. After completion of the reaction, the reaction product was poured into 1 l of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was adjusted to pH4 with concentrated hydrochloric acid, and precipitated crystals were collected by filtration and dried to obtain 26.2 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 164° to 165° C.

(2) 45 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 112.5 ml of acetic acid. While heating it to a temperature of from 100° to 105° C., 26 g of fuming nitric acid (94%) was dropwise added, and the mixture was reacted for further 6 hours. The reaction product was left to cool to 80° C., and then poured into 2 l of ice water. Precipitated crystals were collected by filtration, washed with water and dried to obtain 47.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.

(3) 3.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was suspended in a solvent mixture comprising 30 ml of water and 30 ml of acetic acid, and 2.2 g of reduced iron was added thereto. Then, the mixture was heated to 50° C. and reacted for one hour. After completion of the reaction, the reaction product was cooled to room temperature, and excess iron was separated by filtration. The filtrate was extracted with ethyl acetate. The extract layer was washed with water and dried. Ethyl acetate was distilled off under reduced pressure to obtain 2.5 g of N-(3-amino-5-trifluoromethylethyl-2-pyridyl)ethanesulfonamide.

An alternative process will be described. To a solution prepared by dissolving 34.9 g of sodium hydrosulfite in 400 ml of water, a solution prepared by dissolving 5.0 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)ethanesulfonamide in 80 ml of tetrahydrofuran, was dropwise added at room temperature. After completion of the dropwise addition, the mixture was reacted for further 3 hours. After completion of the reaction, sodium chloride was added until the tetrahydrofuran layer was separated. The separated tetrahydrofuran layer was dried, and tetrahydrofuran was distilled off under reduced pressure to obtain 4.2 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide.

(4) 2.36 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 24 ml of dry tetrahydrofuran, and 1.54 g of cyclohexanecarbonyl chloride was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained crystals were washed with ethyl ether to obtain 2.94 g of the desired product having a melting point of from 153° to 155° C.

An alternative process will be described. In 20 ml of methylene chloride, 0.5 g of 4-diemthylaminopyridine was dissolved, and 0.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and dissolved. Then, 1 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was added thereto, and 30 minutes later, 0.52 g of cyclohexane-carboxylic acid was added thereto, and stirring was conducted for 10 hours. After completion of the reaction, 40 ml of methylene chloride was added to the reaction product, and the reaction product was washed with 10% hydrochloric acid and then washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. From the extract layer, solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the desired product.

PREPARATION EXAMPLE 5 Preparation of sodium salt of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide (Compound No. 251)

To 10 ml of an ethanol solution containing 1.00 g of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, 2.75 g of a 1N-sodium hydroxide aqueous solution was added under stirring at 40° C., and the mixture was stirred for one hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with ethyl ether to obtain 1.02 g of the desired product which decomposed at 299° C.

Trifluoromethylpyridine compounds of the above formula (VIII) are listed in Table 1.

                  TABLE 1                                                          ______________________________________                                          ##STR12##                   (VIII)                                            Intermediate                      Melting point                                No.      Q      Y.sup.5           (°C.)                                 ______________________________________                                         1        H      SO.sub.2 CH.sub.3 189˜191                                2        H      SO.sub.2 C.sub.2 H.sub.5                                                                         164˜165                                3        H      SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              157˜159                                4        H      SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     148˜150                                5        H                                                                                      ##STR13##        181˜184                                6        H                                                                                      ##STR14##                                                     7        H      SO.sub.2 CH.sub.2 CHCH.sub.2                                   8        H                                                                                      ##STR15##                                                     9        H      SO.sub.2 CH.sub.2 C(CH.sub.3)CH.sub.2                          10       H      SO.sub.2 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                  11       H      SO.sub.2 CF.sub.3 215˜218                                12       H                                                                                      ##STR16##                                                     13       H                                                                                      ##STR17##                                                     14       H                                                                                      ##STR18##                                                     15       H      SO.sub.2 C.sub.8 H.sub.17 (n)                                  16       H      SO.sub.2 C.sub.18 H.sub.37 (n)                                 17       H      SO.sub.2 CF.sub.2 CF.sub.3                                     18       NO.sub.2                                                                              SO.sub.2 CH.sub.3 138˜139                                19       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.3                                                                       160˜163                                20       NO.sub.2                                                                               ##STR19##        138˜140                                21       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              109˜112                                22       NO.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     76˜78                                  23       NO.sub.2                                                                               ##STR20##        138˜140                                24       NO.sub.2                                                                               ##STR21##        145˜146                                25       NO.sub.2                                                                              NHSO.sub.2 CH.sub.3                                                                              175˜182                                26       NO.sub.2                                                                               ##STR22##                                                     27       NO.sub.2                                                                               ##STR23##                                                     28       NO.sub.2                                                                               ##STR24##                                                     29       NO.sub.2                                                                               ##STR25##        51˜56                                  30       NO.sub.2                                                                               ##STR26##        156˜158                                31       NO.sub.2                                                                               ##STR27##                                                     32       NO.sub.2                                                                               ##STR28##                                                     33       NO.sub.2                                                                               ##STR29##                                                     34       NO.sub.2                                                                               ##STR30##        130˜132                                35       NO.sub.2                                                                               ##STR31##                                                     36       NO.sub.2                                                                               ##STR32##                                                     37       NO.sub.2                                                                               ##STR33##        192˜194                                38       NO.sub.2                                                                               ##STR34##                                                     39       NO.sub.2                                                                               ##STR35##                                                     40       NO.sub.2                                                                               ##STR36##                                                     41       NO.sub.2                                                                               ##STR37##                                                     42       NO.sub.2                                                                               ##STR38##                                                     43       NO.sub.2                                                                               ##STR39##                                                     44       NO.sub.2                                                                               ##STR40##                                                     45       NO.sub.2                                                                               ##STR41##                                                     46       NO.sub.2                                                                               ##STR42##                                                     47       NO.sub.2                                                                               ##STR43##                                                     48       NO.sub.2                                                                               ##STR44##        148˜149                                49       NO.sub.2                                                                               ##STR45##        132                                          50       NO.sub.2                                                                              SO.sub.2 CF.sub.3 126˜127                                51       NO.sub.2                                                                              SO.sub.3 CH.sub.3 93˜94                                  52       NO.sub.2                                                                              SO.sub.3 C.sub.2 H.sub.5                                                                         120˜121                                53       NO.sub.2                                                                               ##STR46##        104˜105                                54       NO.sub.2                                                                               ##STR47##                                                     55       NH.sub.2                                                                              SO.sub.2 CH.sub.3 128˜130                                56       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.3                                                                       118˜ 120                               57       NH.sub.2                                                                               ##STR48##        155˜157                                58       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                              82˜84                                  59       NH.sub.2                                                                              SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                     102˜103                                60       NH.sub.2                                                                               ##STR49##        200˜204                                61       NH.sub.2                                                                               ##STR50##        170˜175                                62       NH.sub.2                                                                              NHSO.sub.2 CH.sub.3                                                                              128˜133                                63       NH.sub.2                                                                               ##STR51##                                                     64       NH.sub.2                                                                               ##STR52##                                                     65       NH.sub.2                                                                               ##STR53##                                                     66       NH.sub.2                                                                               ##STR54##        136˜139                                67       NH.sub.2                                                                               ##STR55##        164˜168                                68       NH.sub.2                                                                               ##STR56##                                                     69       NH.sub.2                                                                               ##STR57##                                                     70       NH.sub.2                                                                               ##STR58##                                                     71       NH.sub.2                                                                               ##STR59##        171˜174                                72       NH.sub.2                                                                               ##STR60##                                                     73       NH.sub.2                                                                               ##STR61##                                                     74       NH.sub.2                                                                               ##STR62##        168˜173                                75       NH.sub.2                                                                               ##STR63##                                                     76       NH.sub.2                                                                               ##STR64##                                                     77       NH.sub.2                                                                               ##STR65##                                                     78       NH.sub.2                                                                               ##STR66##                                                     79       NH.sub.2                                                                               ##STR67##                                                     80       NH.sub.2                                                                               ##STR68##                                                     81       NH.sub.2                                                                               ##STR69##                                                     82       NH.sub.2                                                                               ##STR70##                                                     83       NH.sub.2                                                                               ##STR71##                                                     84       NH.sub.2                                                                               ##STR72##                                                     85       NH.sub.2                                                                               ##STR73##        165˜167                                86       NH.sub.2                                                                               ##STR74##        134˜136                                87       NH.sub.2                                                                              SO.sub.2 CF.sub.3 122˜124                                88       NH.sub.2                                                                              SO.sub.3 CH.sub.3  97˜100                                89       NH.sub.2                                                                              SO.sub.3 C.sub.2 H.sub.5                                                                         131˜132                                90       NH.sub.2                                                                               ##STR75##        223˜227                                91       NH.sub.2                                                                               ##STR76##                                                     ______________________________________                                    

Compounds of the above formula (II) which are not included in the compounds of the above formula (VIII) are listed in Table 2.

                  TABLE 2                                                          ______________________________________                                          ##STR77##                    (II)                                             Intermediate                 Melting point                                     No.       Y                  (°C.)                                      ______________________________________                                         100                                                                                       ##STR78##         207˜210                                     101       NHCOOCH.sub.2 CH.sub.3                                                                            187˜192                                     102       COOCH.sub.2 CH.sub.3                                                                              289˜292                                     103       NHCOCH.sub.3                                                         104                                                                                       ##STR79##                                                           105                                                                                       ##STR80##                                                           106       CH.sub.3                                                             107       CH.sub.2 CH.sub.3                                                    108       COCH.sub.3                                                           109       COCH.sub.2 CHCH.sub.2                                                110                                                                                       ##STR81##                                                           111                                                                                       ##STR82##                                                           112                                                                                       ##STR83##                                                           113                                                                                       ##STR84##                                                           114                                                                                       ##STR85##                                                           115                                                                                       ##STR86##                                                           116       COCOCH.sub.3                                                         117                                                                                       ##STR87##                                                           ______________________________________                                    

Compounds of the above formula (III) are listed in Table 3.

                  TABLE 3                                                          ______________________________________                                          ##STR88##                    (III)                                            Intermediate                Melting point                                      No.        X                (°C.)                                       ______________________________________                                         118        COCHCl.sub.2     170˜171                                      119        COCCl.sub.3      141˜143                                      120        COOCH.sub.2 CH.sub.3                                                                            151˜154                                      121                                                                                        ##STR89##       156˜158                                      122        COCOCH.sub.3                                                        123                                                                                        ##STR90##                                                          124        CONHCOCH.sub.3                                                      125                                                                                        ##STR91##                                                          126                                                                                        ##STR92##       248˜251                                      ______________________________________                                    

Compounds of the above formula (IV) which are not included in the compounds of the above formula (VIII) are listed in Table 4.

                  TABLE 4                                                          ______________________________________                                          ##STR93##                    (IV)                                             Intermediate               Melting point                                       No.         Y.sup.2        (°C.)                                        ______________________________________                                         127                                                                                         ##STR94##     189˜195                                       128         NHCOOCH.sub.2 CH.sub.3                                                                        97˜99                                         129         NHCOCH.sub.3                                                       130         CH.sub.3                                                           131         CH.sub.2 CH.sub.3                                                  ______________________________________                                    

Typical specific examples of the compound of the formula (I) of the present invention are listed in Table 5.

                                      TABLE 5                                      __________________________________________________________________________      ##STR95##                                        (I)                          Compound                              Type of                                                                             Melting point                       No.   X                Y              salt (°C.)                        __________________________________________________________________________     1     CO(CH.sub.2).sub.2 CH.sub.3                                                                     SO.sub.2 CH.sub.3   113˜114                       2     CO(CH.sub.2).sub.3 CH.sub.3                                                                     SO.sub.2 CH.sub.3   119˜121                       3     CO(CH.sub.2).sub.4 CH.sub.3                                                                     SO.sub.2 CH.sub.3   119˜122                       4     CO(CH.sub.2).sub.7 CH.sub.3                                                                     SO.sub.2 CH.sub.3    99˜101                       5     CO(CH.sub.2).sub.10 CH.sub.3                                                                    SO.sub.2 CH.sub.3    94˜97                        6     CO(CH.sub.2).sub.14 CH.sub.3                                                                    SO.sub.2 CH.sub.3    99˜103                       7     COCH.sub.2 C(CH.sub.3).sub.3                                                                    SO.sub.2 CH.sub.3   150˜151                              ##STR96##       SO.sub.2 CH.sub.3   110˜116                       9     COCHCH.sub.2     SO.sub.2 CH.sub.3   174˜ 176                      10                                                                                    ##STR97##       SO.sub.2 CH.sub.3   211˜213                       11    COCF.sub.2 Cl    SO.sub.2 CH.sub.3   199˜201                       12    COCF.sub.3       SO.sub.2 CH.sub.3   154˜157                       13    COCF.sub.2 CF.sub.3                                                                             SO.sub.2 CH.sub.3   186˜189                       14    COCF.sub.2 CF.sub.2 CF.sub.3                                                                    SO.sub.2 CH.sub.3   170˜173                       15    COOC.sub.2 H.sub.5                                                                              SO.sub.2 CH.sub.3   180˜182                       16    COO(CH.sub.2).sub.2 CH.sub.3                                                                    SO.sub.2 CH.sub.3   173-176                             17    COO(CH.sub.2).sub.3 CH.sub.3                                                                    SO.sub.2 CH.sub.3   127˜129                       18    CSNHCOOC.sub.2 H.sub.5                                                                          SO.sub.2 CH.sub.3   More than 300                       19    COCF.sub.2 CF.sub.3                                                                             SO.sub.2 C.sub.2 H.sub.5                                                                           168-170                             20    COCF.sub.2 Cl    SO.sub.2 C.sub.2 H.sub.5                                                                           171˜174                       21    CSNHCOOC.sub.2 H.sub.5                                                                          SO.sub.2 C.sub.2 H.sub.5                                                                           More than 300                       22    COCF.sub.2 CF.sub.3                                                                             SO.sub.2 C.sub.3 H.sub.7 (n)                                                                       129˜133                       23    COCF.sub.2 CF.sub.3                                                                             SO.sub.2 C.sub.8 H.sub.17 (n)                                                                      109˜112                       24    COCF.sub.3                                                                                       ##STR98##          160-163                             25    CSNHCOOC.sub.2 H.sub.5                                                                           ##STR99##          195˜200                       26    CO(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                             CO(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                                 75˜76                        27    COCF.sub.3       COCHCl.sub.2        117˜119                       28    COCHCl.sub.2     COCHCl.sub.2        158˜159                       29    COCHCl.sub.2     COCF.sub.3          177˜178                       30    COCCl.sub.3      COCF.sub.3          166˜168                       31                                                                                    ##STR100##      SO.sub.2 C.sub.2 H.sub.5                                                                           135˜137                       32                                                                                    ##STR101##      COCF.sub.2 CF.sub.3 228˜230                       33                                                                                    ##STR102##      SO.sub.2 C.sub.2 H.sub.5                                                                           130˜134                       34                                                                                    ##STR103##      SO.sub.2 CH.sub.3   218˜222                       35                                                                                    ##STR104##      SO.sub.2 CH.sub.3   219˜224                       36                                                                                    ##STR105##      SO.sub.2 C.sub.2 H.sub.5                                37    COOC.sub.2 H.sub.5                                                                              COOC.sub.2 H.sub.5  112˜114                       38                                                                                    ##STR106##      COOC.sub.2 H.sub.5  134˜137                       39    COCF.sub.2 CF.sub.3                                                                              ##STR107##         214˜217                       40    COCF.sub.2 CF.sub.3                                                                             NHSO.sub.2 CH.sub.3 136˜138                       41    COCF.sub.2 CF.sub.3                                                                             CH.sub.3             89˜90                        42                                                                                    ##STR108##                                                                                      ##STR109##                                             43                                                                                    ##STR110##      SO.sub.2 CH.sub.3   189˜192                       44                                                                                    ##STR111##      SO.sub.2 CH.sub.3   217˜220                       45                                                                                    ##STR112##      SO.sub.2 CH.sub.3   153-155                             46    CO(CH.sub.2).sub.4 Cl                                                                           SO.sub.2 CH.sub.3    79˜85                        47                                                                                    ##STR113##      SO.sub.2 CH.sub.2 CH.sub.3                                                                         153˜155                       48                                                                                    ##STR114##      SO.sub.2 CH.sub.2 CH.sub.3                                                                         204˜210                       49    COCHCH.sub.2     SO.sub.2 CH.sub.2 CH.sub.3                                                                         148˜151                       50    COCCl.sub.3                                                                                      ##STR115##         178˜180                       51    COCF.sub.2 CF.sub.3                                                                              ##STR116##         161˜163                       52    COCF.sub.2 CF.sub.3                                                                             SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                       146˜149                       53                                                                                    ##STR117##      SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                       152˜154                       54    CSNHCOOC.sub.2 H.sub.5                                                                          CH.sub.3            191˜193                       55    COCHCHCH.sub.3   SO.sub.2 CH.sub.3   158˜161                       56                                                                                    ##STR118##      SO.sub.2 C.sub.2 H.sub.5                                                                           234˜237                       57                                                                                    ##STR119##      SO.sub.2 CH.sub.3   210˜214                       58                                                                                    ##STR120##      SO.sub.2 CH.sub.3   220˜222                       59    COCF.sub.2 CF.sub.2 H                                                                           SO.sub.2 C.sub.2 H.sub.5                                60                                                                                    ##STR121##      SO.sub.2 CH.sub.3   163˜166                       61                                                                                    ##STR122##      SO.sub.2 CH.sub.3   172˜174                       62                                                                                    ##STR123##      SO.sub.2 CH.sub.3   147˜ 148                      63    COCH.sub.2 OCOCH.sub.3                                                                          SO.sub.2 CH.sub.3   155˜156                       64                                                                                    ##STR124##      SO.sub.2 CH.sub.3   163˜165                       65    COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.3 CH.sub.3                                                  SO.sub.2 CH.sub.3   141˜144                       66                                                                                    ##STR125##      SO.sub.2 CH.sub.3   128˜130                       67                                                                                    ##STR126##      SO.sub.2 CH.sub.3   126˜130                       68                                                                                    ##STR127##      SO.sub.2 CH.sub.3   143˜145                       69                                                                                    ##STR128##      SO.sub.2 CH.sub.3   176˜179                       70    COCHC(CH.sub.3).sub.2                                                                           SO.sub.2 CH.sub.3   187˜188                       71                                                                                    ##STR129##      SO.sub.2 CH.sub.3   215˜218                       72                                                                                    ##STR130##      SO.sub.2 CH.sub.3   227˜229                       73    COCHCHCHCHCH.sub.3                                                                              SO.sub.2 CH.sub.3   300                                 74    CO(CH.sub.2).sub.2 CHCH.sub.2                                                                   SO.sub.2 CH.sub.3    91˜93                        75                                                                                    ##STR131##      SO.sub.2 CH.sub.3   209˜210                       76                                                                                    ##STR132##      SO.sub.2 CH.sub.3   245˜249                       77                                                                                    ##STR133##      SO.sub.2 CH.sub.3   229˜231                       78                                                                                    ##STR134##      SO.sub.2 CH.sub.3   187˜189                       79                                                                                    ##STR135##      SO.sub.2 CH.sub.3   198˜201                       80                                                                                    ##STR136##      SO.sub.2 CH.sub.3   230˜233                       81                                                                                    ##STR137##      SO.sub.2 CH.sub.3   211˜215                       82                                                                                    ##STR138##      SO.sub.2 CH.sub.3   206˜210                       83                                                                                    ##STR139##      SO.sub.2 CH.sub.3   207˜210                       84                                                                                    ##STR140##      SO.sub.2 CH.sub.3   202˜205                       85                                                                                    ##STR141##      SO.sub.2 CH.sub.3   227˜231                       86                                                                                    ##STR142##      SO.sub.2 CH.sub.3   250˜252                       87                                                                                    ##STR143##      SO.sub.2 CH.sub.3   194˜197                       88                                                                                    ##STR144##      SO.sub.2 CH.sub.3   229˜233                       89    COCCl.sub.2 CH.sub.3                                                                            SO.sub.2 CH.sub.3   212˜214                       90                                                                                    ##STR145##       SO.sub.2 CH.sub.3  231˜234                       91                                                                                    ##STR146##      SO.sub.2 CF.sub.3   175˜178                       92                                                                                    ##STR147##      SO.sub.2 CF.sub.3   209˜210                       93    COCHCHCH.sub.3   SO.sub.2 C.sub.2 H.sub.5                                                                           158˜160                       94                                                                                    ##STR148##      SO.sub.2 C.sub.2 H.sub.5                                                                           157˜161                       95                                                                                    ##STR149##      SO.sub.2 C.sub.2 H.sub.5                                                                           147˜148                       96                                                                                    ##STR150##      SO.sub.2 C.sub.2 H.sub.5                                                                           163˜165                       97                                                                                    ##STR151##      SO.sub.2 C.sub.2 H.sub.5                                                                           163˜166                       98                                                                                    ##STR152##      SO.sub.2 C.sub.2 H.sub.5                                                                           204˜208                       99                                                                                    ##STR153##      SO.sub.2 C.sub.2 H.sub.5                                                                           215˜218                       100                                                                                   ##STR154##      SO.sub.2 C.sub.2 H.sub.5                                                                           233˜237                       101                                                                                   ##STR155##      SO.sub.2 C.sub.2 H.sub.5                                                                           208˜209                       102                                                                                   ##STR156##      SO.sub.2 C.sub.2 H.sub.5                                                                           188˜190                       103                                                                                   ##STR157##      SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                     152˜154                       104                                                                                   ##STR158##      SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                     216˜217                       105                                                                                   ##STR159##      SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                     227˜230                       106   COOC.sub.3 H.sub.7 (n)                                                                          SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                     161˜163                       107                                                                                   ##STR160##      SO.sub.2 C.sub.4 H.sub.9 (n)                                                                       138˜139                       108   COCF.sub.2 Cl    SO.sub.2 C.sub.4 H.sub.9 (n)                                                                       156                                 109                                                                                   ##STR161##                                                                                      ##STR162##         202˜205                       110   CO(CH.sub.2).sub.4 CH.sub.3                                                                     SO.sub.2 N(CH.sub.3).sub.2                                                                          97                                 111                                                                                   ##STR163##      SO.sub.2 N(CH.sub.3).sub.2                                                                         168˜169                       112   COCF.sub.2 CF.sub.3                                                                             SO.sub.2 N(CH.sub.3).sub.2                                                                         157˜159                       113                                                                                   ##STR164##      SO.sub.2 N(CH.sub.3).sub.2                                                                         189˜191                       114   COOC.sub.3 H.sub.7 (n)                                                                          SO.sub.2 N(CH.sub.3).sub.2                                                                         174˜176                       115                                                                                   ##STR165##      SO.sub.2 OCH.sub.3  147˜148                       116                                                                                   ##STR166##      SO.sub.2 OCH.sub.3  163˜164                       117                                                                                   ##STR167##      SO.sub.2 OC.sub.2 H.sub.5                                                                          140˜141                       118                                                                                   ##STR168##      SO.sub.2 OC.sub. 2 H.sub.5                                                                         160˜162                       119                                                                                   ##STR169##      SO.sub.2 C.sub.2 H.sub.5                                                                           137˜139                       120                                                                                   ##STR170##      SO.sub.2 CH.sub.3   202˜203                       121                                                                                   ##STR171##      SO.sub.2 CH.sub.3   145˜147                       122                                                                                   ##STR172##      SO.sub.2 CH.sub.3   221˜224                       123                                                                                   ##STR173##      SO.sub.2 CH.sub.3   184˜185                       124   CO(CH.sub.2).sub.5 CH.sub.3                                                                     SO.sub.2 CH.sub.3    94˜96                        125   CO(CH.sub.2).sub.6 CH.sub.3                                                                     SO.sub.2 CH.sub.3    94˜96                        126                                                                                   ##STR174##                                                                                      ##STR175##         178˜180                       127                                                                                   ##STR176##                                                                                      ##STR177##         226˜228                       128                                                                                   ##STR178##      SO.sub.2 CH.sub.3                                       129                                                                                   ##STR179##      SO.sub.2 CH.sub.3                                       130                                                                                   ##STR180##      SO.sub.2 CH.sub.3                                       131                                                                                   ##STR181##      SO.sub.2 CH.sub.3                                       132                                                                                   ##STR182##      SO.sub.2 CH.sub.3                                       133                                                                                   ##STR183##                                                                                      ##STR184##                                             134                                                                                   ##STR185##                                                                                      ##STR186##                                             135                                                                                   ##STR187##                                                                                      ##STR188##                                             136                                                                                   ##STR189##      SO.sub.2 C.sub.2 H.sub.5                                137                                                                                   ##STR190##                                                                                      ##STR191##                                             138                                                                                   ##STR192##                                                                                      ##STR193##                                             139                                                                                   ##STR194##                                                                                      ##STR195##         138˜140                       140                                                                                   ##STR196##                                                                                      ##STR197##         190˜192                       141                                                                                   ##STR198##                                                                                      ##STR199##                                             142                                                                                   ##STR200##      SO.sub.2 C.sub.2 H.sub.5                                                                           210˜211                       143                                                                                   ##STR201##      SO.sub.2 C.sub.2 H.sub.5                                144                                                                                   ##STR202##      SO.sub.2 C.sub.2 H.sub.5                                145                                                                                   ##STR203##                                                                                      ##STR204##                                             146                                                                                   ##STR205##      SO.sub.2 C.sub.2 H.sub.5                                147                                                                                   ##STR206##      SO.sub.2 C.sub.2 H.sub.5                                148                                                                                   ##STR207##      SO.sub.2 C.sub.2 H.sub.5                                149                                                                                   ##STR208##      SO.sub.2 C.sub.2 H.sub.5                                150                                                                                   ##STR209##                                                                                      ##STR210##                                             151                                                                                   ##STR211##                                                                                      ##STR212##                                             152                                                                                   ##STR213##      SO.sub.2 C.sub.2 H.sub.5                                153                                                                                   ##STR214##                                                                                      ##STR215##                                             154                                                                                   ##STR216##                                                                                      ##STR217##         166˜167                       155                                                                                   ##STR218##                                                                                      ##STR219##         144˜146                       156                                                                                   ##STR220##                                                                                      ##STR221##                                             157                                                                                   ##STR222##      SO.sub.2 C.sub.2 H.sub.5                                158                                                                                   ##STR223##      SO.sub.2 C.sub.2 H.sub.5                                159                                                                                   ##STR224##                                                                                      ##STR225##                                             160                                                                                   ##STR226##                                                                                      ##STR227##                                             161                                                                                   ##STR228##      SO.sub.2 C.sub.2 H.sub.5                                162                                                                                   ##STR229##                                                                                      ##STR230##         133˜135                       163                                                                                   ##STR231##      SO.sub.2 C.sub.2 H.sub.5                                164                                                                                   ##STR232##      SO.sub.2 C.sub.2 H.sub.5                                165                                                                                   ##STR233##      SO.sub.2 C.sub.2 H.sub.5                                166                                                                                   ##STR234##      SO.sub.2 C.sub.2 H.sub.5                                167                                                                                   ##STR235##                                                                                      ##STR236##                                             168                                                                                   ##STR237##      SO.sub.2 C.sub.2 H.sub.5                                169                                                                                   ##STR238##      SO.sub.2 C.sub.2 H.sub.5                                170                                                                                   ##STR239##      SO.sub.2 C.sub.2 H.sub.5                                171                                                                                   ##STR240##      SO.sub.2 C.sub.2 H.sub.5                                172                                                                                   ##STR241##      SO.sub.2 C.sub.2 H.sub.5                                173                                                                                   ##STR242##      SO.sub.2 C.sub.2 H.sub.5                                174                                                                                   ##STR243##      SO.sub.2 C.sub.2 H.sub.5                                175                                                                                   ##STR244##      SO.sub.2 C.sub.2 H.sub.5                                176                                                                                   ##STR245##      SO.sub.2 C.sub.2 H.sub.5                                177                                                                                   ##STR246##      SO.sub.2 C.sub.2 H.sub.5                                178                                                                                   ##STR247##      SO.sub.2 C.sub.2 H.sub.5                                179                                                                                   ##STR248##      SO.sub.2 C.sub.2 H.sub.5                                180                                                                                   ##STR249##      SO.sub.2 C.sub.2 H.sub.5                                181                                                                                   ##STR250##      SO.sub.2 C.sub.2 H.sub.5                                182                                                                                   ##STR251##      SO.sub.2 C.sub.2 H.sub.5                                183                                                                                   ##STR252##      SO.sub.2 C.sub.2 H.sub.5                                184                                                                                   ##STR253##                                                                                      ##STR254##                                             185                                                                                   ##STR255##      SO.sub.2 C.sub.2 H.sub.5                                186                                                                                   ##STR256##                                                                                      ##STR257##                                             187                                                                                   ##STR258##      SO.sub.2 C.sub.2 H.sub.5                                188                                                                                   ##STR259##      SO.sub.2 C.sub.2 H.sub.5                                189                                                                                   ##STR260##      SO.sub.2 C.sub.2 H.sub.5                                190                                                                                   ##STR261##      SO.sub.2 C.sub.2 H.sub.5                                191                                                                                   ##STR262##                                                                                      ##STR263##                                             192                                                                                   ##STR264##      SO.sub.2 C.sub.2 H.sub.5                                193                                                                                   ##STR265##      SO.sub.2 C.sub.2 H.sub.5                                194                                                                                   ##STR266##      SO.sub.2 C.sub.2 H.sub.5                                195                                                                                   ##STR267##      SO.sub.2 C.sub.2 H.sub.5                                196                                                                                   ##STR268##      SO.sub.2 C.sub.2 H.sub.5                                197                                                                                   ##STR269##      SO.sub.2 C.sub.2 H.sub.5                                198                                                                                   ##STR270##      SO.sub.2 C.sub.2 H.sub.5                                199                                                                                   ##STR271##      SO.sub.2 C.sub.2 H.sub.5                                200                                                                                   ##STR272##      SO.sub.2 C.sub.2 H.sub.5                                201                                                                                   ##STR273##      SO.sub.2 C.sub.2 H.sub.5                                202                                                                                   ##STR274##      SO.sub.2 C.sub.2 H.sub.5                                203                                                                                   ##STR275##                                                                                      ##STR276##                                             204                                                                                   ##STR277##      SO.sub.2 C.sub.2 H.sub.5                                205                                                                                   ##STR278##      SO.sub.2 C.sub.2 H.sub.5                                206                                                                                   ##STR279##      SO.sub.2 C.sub.2 H.sub.5                                207                                                                                   ##STR280##      SO.sub.2 C.sub.2 H.sub.5                                                                           265˜266                       208                                                                                   ##STR281##                                                                                      ##STR282##                                             209                                                                                   ##STR283##      SO.sub.2 C.sub.2 H.sub.5                                210                                                                                   ##STR284##      SO.sub.2 C.sub.2 H.sub.5                                211                                                                                   ##STR285##      SO.sub.2 C.sub.2 H.sub.5                                212                                                                                   ##STR286##                                                                                      ##STR287##                                             213                                                                                   ##STR288##      SO.sub.2 C.sub.2 H.sub.5                                214                                                                                   ##STR289##      SO.sub.2 C.sub.2 H.sub.5                                                                           248˜249                       215                                                                                   ##STR290##      SO.sub.2 C.sub.2 H.sub.5                                216                                                                                   ##STR291##      SO.sub.2 C.sub.2 H.sub.5                                217                                                                                   ##STR292##      SO.sub.2 C.sub.2 H.sub.5                                                                           219˜221                       218                                                                                   ##STR293##      SO.sub.2 C.sub.2 H.sub.5                                                                           241˜242                       219                                                                                   ##STR294##                                                                                      ##STR295##                                             220                                                                                   ##STR296##      SO.sub.2 C.sub.2 H.sub.5                                221                                                                                   ##STR297##                                                                                      ##STR298##                                             222                                                                                   ##STR299##      SO.sub.2 C.sub.2 H.sub.5                                223                                                                                   ##STR300##      SO.sub.2 C.sub.2 H.sub.5                                224                                                                                   ##STR301##      SO.sub.2 C.sub.2 H.sub.5                                225                                                                                   ##STR302##      SO.sub.2 C.sub.2 H.sub.5                                226                                                                                   ##STR303##      SO.sub.2 C.sub.2 H.sub.5                                227                                                                                   ##STR304##      SO.sub.2 C.sub.2 H.sub.5                                228                                                                                   ##STR305##      SO.sub.2 C.sub.2 H.sub.5                                229                                                                                   ##STR306##      SO.sub.2 C.sub.2 H.sub.5                                230                                                                                   ##STR307##      SO.sub.2 C.sub.2 H.sub.5                                231                                                                                   ##STR308##      SO.sub.2 C.sub.2 H.sub.5                                232                                                                                   ##STR309##      SO.sub.2 C.sub.2 H.sub.5                                233                                                                                   ##STR310##      SO.sub.2 C.sub.2 H.sub.5                                234                                                                                   ##STR311##      SO.sub.2 C.sub.2 H.sub.5                                235                                                                                   ##STR312##      SO.sub.2 C.sub.2 H.sub.5                                236                                                                                   ##STR313##      SO.sub.2 C.sub.2 H.sub.5                                237                                                                                   ##STR314##      SO.sub.2 C.sub.2 H.sub.5                                238                                                                                   ##STR315##      SO.sub.2 C.sub.2 H.sub.5                                239                                                                                   ##STR316##      SO.sub.2 C.sub.2 H.sub.5                                240                                                                                   ##STR317##      SO.sub.2 C.sub.2 H.sub.5                                241                                                                                   ##STR318##      SO.sub.2 C.sub.2 H.sub.5                                242                                                                                   ##STR319##      SO.sub.2 C.sub. 2 H.sub.5                               243                                                                                   ##STR320##      SO.sub.2 C.sub.2 H.sub.5                                244                                                                                   ##STR321##      SO.sub.2 C.sub.2 H.sub.5                                245                                                                                   ##STR322##      SO.sub.2 C.sub.2 H.sub.5                                246                                                                                   ##STR323##                                                                                      ##STR324##                                             247                                                                                   ##STR325##      SO.sub.2 C.sub.2 H.sub.5                                248                                                                                   ##STR326##                                                                                      ##STR327##                                             249                                                                                   ##STR328##      SO.sub.2 C.sub.3 H.sub.7 (n)                            250                                                                                   ##STR329##      SO.sub.2 C.sub.3 H.sub.7 (n)                            251                                                                                   ##STR330##      SO.sub.2 C.sub.2 H.sub.5                                                                      Na salt                                                                             299 (decomposed)                    252                                                                                   ##STR331##      SO.sub.2 C.sub.2 H.sub.5                                                                      K salt                                                                              More than 300                       253                                                                                   ##STR332##      SO.sub.2 C.sub.3 H.sub.7 (iso)                                                                Na salt                                  254                                                                                   ##STR333##      SO.sub.2 CF.sub.3                                                                             Na salt                                  255                                                                                   ##STR334##                                                                                      ##STR335##    Na salt                                  256                                                                                   ##STR336##      SO.sub.2 C.sub.2 H.sub.5                                                                      Na salt                                  257                                                                                   ##STR337##      SO.sub.2 C.sub.2 H.sub.5                                                                      Na salt                                  258                                                                                   ##STR338##      SO.sub.2 C.sub.2 H.sub.5                                                                      Na salt                                  259                                                                                   ##STR339##      SO.sub.2 CH.sub.3                                                                             Na salt                                                                             More than 300                       260   COCF.sub.2 CF.sub.3                                                                             SO.sub.2 CH.sub.3                                                                             Na salt                                                                             More than 300                       261   COCF.sub.2 CF.sub.3                                                                             SO.sub.2 C.sub.2 H.sub.5                                                                      Na salt                                  262                                                                                   ##STR340##      SO.sub.2 C.sub.2 H.sub.5                                                                      Ca salt                                                                             245 (decomposed)                    __________________________________________________________________________

The compound of the formula (I) of the present invention is useful as an active ingredient for a phospholipase A₂ inhibitor, an anti-inflammatory agent or an anti-pancreatitis agent. Phospholipase A₂ can be detected in various tissues or cells in a body. It is said that in platelets or cells related to inflammatory symptoms, phospholipase A₂ is secreted or activated by various stimulations and contributes to the production of a platelet activating factor (PAF) or some arachidonic acid methabolites. The arachidonic acid methabolites have been found to be closely related to various diseases, for example, inflammatory symptoms such as rheumatoid arthritis, arthritis deformans, tenontitis, psoriasis and related dermatitis; nasal and bronchial airway troubles such as allergic rhinitis and allergic bronchial asthma; and immediate hypersensitive reactions such as allergic conjunctivitis. On the other hand, phospholipase A₂ secreted from pancreas is activated in the intestine and exhibits a digestive action, but once activated in the pancreas, it is believed to be one of the factors causing pancreatitis. The compound of the present invention inhibits phospholipase A₂ and thus is effective for the treatment of the above-mentioned diseases caused by phospholipase A.sub. 2 such as inflammatory symptoms, nasal and bronchial airway troubles, immediate hypersensitive reactions or pancreatitis. Thus, it is useful as an anti-inflammatory agent, an agent for treating bronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, anti-nephritis agent, or anti-MOFC (Multiple Organ Failure).

In regard to the efficacy against pancreatitis, the compound of the present invention is expected to be more efficient by using in combination with other drugs, for example, a proteinase inhibitor, such as galexate mesilate, camostat mesilate, or nafamostat mesilate.

The compound of the present invention is particularly suitable for use as an anti-inflammatory agent and/or an anti-pancreatitis agent.

TEST EXAMPLE 1 Phospholipase A₂ inhibitory activity, method A (1) Preparation of substrate

To 10 mg of egg yolk lecithin (manufactured by Wako Pure Chemical Industries Ltd.), 1 ml of glycerine, 2 ml of a 50 mM Tris-HCl buffer solution (pH7.5) [Tris(hydroxymethyl)aminomethane (manufactured by Nacalai Tesque K.K.) was adjusted to pH7.5 with hydrochloric acid], 0.5 ml of a 150 mM calcium chloride solution (calcium chloride was dissolved in a 50 mM Tris-HCl buffer solution) and 0.5 ml of a 0.05% Triton-X100 (manufactured by Nacalai Tesque K.K.) solution (Triton-X100 was dissolved in a 50 mM Tris-HCl buffer solution), were added and dispersed by an agate mortar or dispersed by an ultrasonic processor (Model W-225, manufactured by Heat System-Ultrasonics, Inc.) for 5 minutes (30W) to obtain a substrate.

(2) Enzyme

Porcine pancreatic phospholipase Az [(161454.122416) manufactured by Boehringer Mannheim.Yamanouchi K.K.] was used.

(3) Measurement of phospholipase A₂ activity

To a 96 well microtitration plate (flat bottom, manufactured by Sumitomo Bakelite Medical Co., Ltd.), 40 μl of the substrate, 5 μl of a solution prepared by dissolving 10 mg of a test compound in 500 μl of dimethylsulfoxide, followed by an addition of 500 μl of a 50 mM Tris-HCl buffer solution, and 5 μl of an enzyme solution of 20 ng/ml (prepared by diluting the enzyme in a 50 mM Tris-HCl buffer solution), were added and reacted at 37° C. for 30 minutes. After termination of the reaction, the released free fatty acid was quantitatively analyzed in accordance with the ACS-ACOD (acyl CoA synthetase-acyl CoA oxidase) method [a kit of NEFA C test wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used]. The quantitative analysis was made by means of Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories) at a wavelength of 540 nm. Separately, such experiments as mentioned above, were carried out at various concentrations (2 μg/ml, 1 μg/ml and 0.5 μg/ml) of phospholipase A₂ without a test compound. Then, the concentration of the free fatty acid versus the concentration of phospholipase A₂ was plotted.

From this standard curve, the apparent concentration of phospholipase A₂ in the case with a test compound, was read. Then, the percent inhibition of the enzyme was calculated by the following formula. The results are shown in Table 6. ##EQU1##

A: Apparent enzyme concentration when a test compound is added.

B: True enzyme concentration when a test compound is added.

                  TABLE 6                                                          ______________________________________                                                       % inhibition                                                     Compound      of PLA.sub.2                                                     No.           (1,000 ppm)                                                      ______________________________________                                          1            45                                                                2            55                                                                3            67                                                                4            74                                                                5            39                                                                8            81                                                                9            71                                                               10            60                                                               11            52                                                               12            89                                                               13            87                                                               14            54                                                               15            62                                                               16            43                                                               17            46                                                               18            64                                                               19            >90                                                              20            74                                                               21            62                                                               22            74                                                               23            37                                                               24            66                                                               26            35                                                               27            62                                                               28            71                                                               29            47                                                               30            87                                                               32            50                                                               38            35                                                               39            41                                                               41            89                                                               43            47                                                               44            43                                                               45            50                                                               46            47                                                               47            75                                                               48            48                                                               49            30                                                               50            78                                                               51            63                                                               52            49                                                               53            37                                                               54            37                                                               55            49                                                               57            57                                                               58            74                                                               ______________________________________                                    

TEST EXAMPLE 2 Phospholipase A₂ inhibitory activity, method B (1) Preparation of substrate

To a solution prepared by dissolving 9.2 mg of L-α-dipalmitoylphosphatidylcholine (manufactured by Nichiyu Liposome K.K.) in 0.5 ml of chloroform, a solution prepared by dissolving 32 mg of sodium cholate (manufactured by Wako Pure Chemical Industries, Ltd.) in 0.5 ml of methanol, was added, followed by mixing. The solvent of the mixture was removed under a nitrogen stream, and then 2.5 ml of a 250 mM sodium chloride solution [prepared by dissolving sodium chloride in a 100 mM Tris-HCl buffer solution {tris(hydroxymethyl)aminomethane (manufactured by Nacalai Tesque K.K.) was adjusted to pH8.0 with hydrochloric acid}] was added thereto, and the mixture was dissolved under stirring to obtain a substrate.

(2) Enzyme

Porcine pancreatic phospholipase A₂ [(161454.122416) manufactured by Boehringer Mannheim.Yamanouchi K.K.]was used.

(3) Measurement of phospholipase A₂ activity

To a 96 well microtitration plate, 20 μl of a solution containing calcium chloride, bovine serum alubmin (manufactured by Sigma Chemical, Co.) and a Tris-HCl buffer solution (pH8.0) at concentrations of 25 mM, 4.5 mg/ml and 100 mM, respectively, 5 μl of a solution prepared by dissolving 10 mg of a test compound in 500 μl of diemthylsulfoxide, followed by an addition of 500 μl of a 200 mM Tris-HCl buffer solution, 5 μl of an enzyme solution (10 μg/ml) [prepared by dissolving the enzyme in a bovine serum alubmin solution (prepared by dissolving bovine serum alubmin in a 100 mM Tris-HCl buffer solution at a concentration of 1 mg/ml)] and 20 μl of the substrate, were added and reacted at 37° C. for 30 minutes. After termination of the reaction, the released free fatty acid was quantitatively analyzed in accordance with the ACS-ACOD (acyl CoA synthetase-acyl CoA oxidase) method [a kit of NEFA C test wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used]. The quantitative analysis was made by means of Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories) at a wavelength of 540 nm. Separately, such experiments as mentioned above, were carried out at various concentrations (1 μg/ml, 0.75 μg/ml, 0.5 μg/mol and 0.25 μg/ml) of phospholipase A₂ without a test compound. Then, the concentration of the free fatty acid versus the concentration of phospholipase A₂ was plotted.

From this standard curve, the apparent concentration of phospholipase A₂ in the case with a test compound, was read. Then, the percent inhibition of the enzyme was calculated by the following formula. The results are shown in Table 7. ##EQU2##

A: Apparent enzyme concentration when a test compound is added.

B: True enzyme concentration when a test compound is added.

                  TABLE 7                                                          ______________________________________                                                       % inhibition                                                     Compound      of PLA.sub.2                                                     No.           (1,000 ppm)                                                      ______________________________________                                          7            50                                                               10            51                                                               13            51                                                               18            49                                                               19            75                                                               43            49                                                               44            64                                                               45            41                                                               47            90                                                               53            100                                                              58            42                                                               60            41                                                               61            36                                                               62            53                                                               63            34                                                               64            61                                                               65            71                                                               66            52                                                               67            82                                                               68            81                                                               69            63                                                               70            40                                                               71            77                                                               72            73                                                               73            53                                                               74            33                                                               75            81                                                               76            61                                                               77            61                                                               78            51                                                               79            65                                                               80            73                                                               81            94                                                               82            38                                                               83            64                                                               84            56                                                               85            33                                                               86            93                                                               87            88                                                               88            83                                                               89            51                                                               90            79                                                               91            81                                                               92            75                                                               93            48                                                               94            63                                                               95            85                                                               97            88                                                               98            65                                                               99            86                                                               100           83                                                               103           86                                                               104           61                                                               106           78                                                               108           61                                                               109           67                                                               110           58                                                               111           41                                                               112           79                                                               113           35                                                               114           53                                                               115           52                                                               116           69                                                               117           65                                                               118           84                                                               121           90                                                               122           56                                                               123           86                                                               124           78                                                               125           86                                                               126           84                                                               127           89                                                               251           85                                                               259           61                                                               260           53                                                               ______________________________________                                    

TEST EXAMPLE 3 Inhibitory activity on increased vascular permeability induced by acetic acid (Mouse Whittle method, method C

Using ddy male mice, each test group consisted of 4 or 5 mice. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. A test compound was orally administered, and upon expiration of one hour from the administration, 0.7% acetic acid was intraperitonially injected to each mouse in an amount of 0.1 ml/10 g, and at the same time, 2% brilliant blue was intravenously injected into the tail vein in an amount of 0.1 ml/20 g. Thirty minutes after the injection of brilliant blue, the cervical vertebrae were dislocated under anesthesia by chloroform, and the abdorminal cavity was washed with 5 ml of a physiological saline. The washing solution was subjected to centrifugal separation at 3,000 rpm for 10 minutes, and the amount of the dye in the supernatant was measured at 600 nm absorbance by Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories). The inhibition rate of the amount of leaked dye in the group in which a test compound was administered relative to the control group was obtained by the following formula. The results are shown in Table 8. ##EQU3##

C: Amount of leaked dye in the group to which a test compound was administered.

D: Amount of leaked dye in the control group.

                  TABLE 8                                                          ______________________________________                                                                  Inhibition                                            Compound        Dose     rate                                                  No.             (mg/kg)  (%)                                                   ______________________________________                                          1              50       46                                                     2              20       51                                                     3              50       58                                                     4              50       43                                                     5              50       53                                                     7              20       53                                                     8              20       48                                                     9              50       81                                                    10              25       53                                                                    10       42                                                    11              100      49                                                    13              100      57                                                    15              50       41                                                    16              20       55                                                    17              50       31                                                    18              25       49                                                    20              20       48                                                    22              20       81                                                                    10       39                                                    23              20       33                                                    39              20       53                                                    41              100      85                                                    43              20       48                                                    45              20       29                                                    47              20       72                                                                    10       46                                                    49              20       50                                                    55              25       59                                                    57              20       43                                                    63              10       41                                                    78              20       51                                                                    10       32                                                    79              20       67                                                    86              20       42                                                    87              10       28                                                    93              20       47                                                                    10       40                                                    94              20       53                                                    101             20       46                                                    120             20       43                                                    251             20       43                                                    ______________________________________                                    

TEST EXAMPLE 4 Inhibitory-activity on increased vascular permeability induced by acetic acid (Rat Whittle method, method D

Using SD (Crj: CD) male rats, each test group consisted of from 3 to 5 rats. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. A test compound was orally administered, and one hour later, 0.7% acetic acid was intraperitonially injected to each rat in an amount of 0.05 ml/10 g, and at the same time, 2% brilliant blue was intravenously injected into the tail vein in an amount of 0.05 ml/20 g. Thirty minutes after the injection of brilliant blue, the cervical vertebrae were dislocated under anesthesia by chloroform, and the abdorminal cavity was washed with 10 ml of a physiological saline. The washing solution was subjected to centrifugal separation at 3,000 rpm for 10 minutes, and the amount of the dye in the supernatant was measured at 600 nm absorbance by Microplate ELISA Reader (Model 2550EIA Reader, manufactured by Bio-Rad Laboratories). The inhibition rate of the amount of leaked dye in the group to which a test compound was administered relative to the control group was obtained from the following formula, and the results are shown in Table 9. ##EQU4##

C: Amount of leaked dye in the group to which a test compound was administered.

D: Amount of leaked dye in the control group.

                  TABLE 9                                                          ______________________________________                                                                  Inhibition                                            Compound        Dose     rate                                                  No.             (mg/kg)  (%)                                                   ______________________________________                                          2              100      38                                                     3              100      75                                                    10              100      57                                                                    50       37                                                    16              100      96                                                    17              50       40                                                    19              50       34                                                    20              100      49                                                    22              100      58                                                    23              100      40                                                    43              50       72                                                    45              50       27                                                    46              50       31                                                    47              50       82                                                                    25       56                                                    49              50       30                                                    55              25       69                                                                      12.5   43                                                    57              50       47                                                    58              50       31                                                    60              50       72                                                    61              25       61                                                    63              50       39                                                                    25       31                                                    66              25       72                                                    69              25       48                                                    72              25       66                                                    78              50       55                                                                    25       40                                                    79              50       74                                                    80              50       35                                                                    25       33                                                    82              25       38                                                    86              50       37                                                    87              25       61                                                                      12.5   47                                                    93              50       71                                                                    25       54                                                    94              50       55                                                                    25       45                                                    98              50       32                                                    101             50       41                                                    113             50       67                                                    120             100      56                                                                    50       35                                                    121               12.5   31                                                    251             25       70                                                                      12.5   46                                                    ______________________________________                                    

TEST EXAMPLE 5 Inhibitory activity on carrageenin edema

Using Wister male rats (body weight: about 100 g), each test group consisted of 5 rats. A test compound was mixed with Tween 80 [polyoxyethylenesorbitan monooleate (manufactured by Nacalai Tesque K.K.)], and distilled water was added thereto to obtain a 2% Tween 80 suspension, or it was dissolved in the form of a salt in water to obtain an aqueous solution. Either the suspension or the aqueous solution was orally administered in an amount of 200 mg/kg, 100 mg/kg, 50 mg/kg or 25 mg/kg. One hour later, 0.1 ml of a 1% λ-carrageenin solution dissolved in a physiological saline was injected subcutaneously to the right hind paw of each rat to cause inflamation. Three hours later, the paw volume was measured by a paw volume measuring device (manufactured by Ugobasiee K.K.). A swelling volume was obtained from the difference from the value before the inflammation. The inhibition rate was calculated by the following formula, and the results are shown in Table 10. ##EQU5##

F: Average swelling volume in the group to which a test compound was administered.

E: Average swelling volume in the control group.

                  TABLE 10                                                         ______________________________________                                                                  Inhibition                                            Compound        Dose     rate                                                  No.             (mg/kg)  (%)                                                   ______________________________________                                          2              100      17                                                     3              100      20                                                     5              100      37                                                    10              100      28                                                    11              100      24                                                    13              100      21                                                    16              100      24                                                    19              100      31                                                    22              100      29                                                    23              100      30                                                    25              200      27                                                    28              50       25                                                    39              100      25                                                    43              50       31                                                    45              50       23                                                    46              50       30                                                    47              50       41                                                    57              100      35                                                    60              50       27                                                    65              50       37                                                    66              50       31                                                    67              25       19                                                    69              50       25                                                    72              25       21                                                    73              50       20                                                    77              50       22                                                    78              50       26                                                    79              50       20                                                    80              50       29                                                    82              50       19                                                    86              50       27                                                    87              50       21                                                    91              50       23                                                    93              50       22                                                    94              50       23                                                    98              50       45                                                    101             50       24                                                    104             50       48                                                    106             50       19                                                    110             50       25                                                    113             50       26                                                    114             50       28                                                    120             50       27                                                    123             50       42                                                    125             50       22                                                    150             50       23                                                    251             50       30                                                    259             50       17                                                    ______________________________________                                    

TEST EXAMPLE 6 Acute toxicity Administration route: Intravenous injection

Using ddy male mice (body weight: 25-30 g), each test group consisted of 5 mice. A test compound was dissolved in the form of a sodium salt in a physiological saline or in a 5% glucose aqueous solution, and intravenously injected in an amount of 0.1 ml/10 g body weight. After the injection, the mortality rate was obtained over one week, and the median lethal dose LD₅₀ (mg/kg) was determined. The results are shown in Table 11.

                  TABLE 11                                                         ______________________________________                                         Compound      LD.sub.50                                                        No.           (mg/kg)                                                          ______________________________________                                          1            100˜150                                                     2            50˜100                                                      3            >100                                                              8            >25                                                               9            >150                                                             10            50˜100                                                     11            >150                                                             12            >150                                                             13            >70                                                              15            100˜150                                                    16            >100                                                             17            50˜100                                                     18            >150                                                             19            50˜100                                                     21            >75                                                              22            >100                                                             24            >150                                                             40            50˜100                                                     43            78                                                               45            98                                                               47            58                                                               49            175                                                              55            237                                                              57            83                                                               60            >60                                                              61            >80                                                              63            >130                                                             68            >80                                                              73            >80                                                              77            >80                                                              78            >60                                                              80            >80                                                              86            >40                                                              87            75                                                               91            >80                                                              106           >20                                                              120           83                                                               251           65                                                               ______________________________________                                    

TEST EXAMPLE 7 Effects against acute pancreatitis

Using Crj-CD male rats (for Compound No. 19, rats having a body weight of from 371 to 484 g were used, and for Compound No. 10, rats having a body weight of from 444 to 574 g were used), each test group consisted of 3 rats. An experimental acute pancreatitis model was prepared by a closed duodenal loop method under anesthesia with halothane (manufactured by Hoechst Japan) and nitrous oxide (manufactured by Sumitomo Seika K.K.) applied by means of a general inhalation anesthesia machine (Model EM-2 and halothane evaporator F-Model). Then, Compound No. 19 or Compound No. 10 was continuously intravenously injected into the tail vein in an amount of 50 mg per kg or 40 mg per kg, respectively, at a rate of 0.05 ml per minute by means of a pump (Technicon AA II Proportioning Pump III, manufactured by Technicon Instruments Corporation). No injection was made to a control group. Gross pathological examination was conducted upon expiration of 6 hours after the ventrotomy in the case of the test group to which Compound No. 19 was administered, or upon expiration of 3 hours after the ventrotomy in the case of the test group to which Compound No. 10 was administered. As a result, as shown in the following Table 12, the groups to which the compounds of the present invention were administered, show distinct usefulness for treating acute pancreatitis.

                  TABLE 12                                                         ______________________________________                                                    Pancreatic                                                                     hemorrhage  Pancreatic                                                         Petechia    edema                                                                         Distri-         Distri-                                  Groups       Grade    bution   Grade  bution                                   ______________________________________                                         Control group                                                                               ++       ++       ++     ++                                       (against the group to                                                                       ++       ++       +++    ++                                       which Compound No.                                                                          +++      +++      +++    ++                                       19 was administered)                                                           Group to which                                                                              -        -        +      +                                        Compound No. 19                                                                             -        -        ++     ++                                       was administered                                                                            -        -        +      +                                        Control group                                                                               ++       ++       ++     ++                                       (against the group to                                                                       +        +        ++     ++                                       which Compound No.                                                                          ±     ±     ++     ++                                       10 was administered)                                                           Group to which                                                                              ±     ±     ±   ±                                     Compound No. 10                                                                             -        -        +      +                                        was administered                                                                            +        +        ++     +                                        ______________________________________                                          Grade of pancreatic lesions                                                    -: No significant lesions,                                                     ±: Minimal,                                                                 +: Light,                                                                      ++: Moderate,                                                                  +++: Marked                                                                    Distribution of pancreatic lesions                                             -: No significant lesions,                                                     ±˜+++: Focaldiffuse                                             

TEST EXAMPLE 8 Effects against acute pancreatitis

Using Crj-CD male rats, each test group consisted of 3 rats. An experimental acute pancreatitis model was prepared by a closed duodenal loop method under anethesia with halothane (manufactured by Hoechst Japan) and nitrous oxide (manufactured by Sumitomo Seika K.K.) applied by a general inhalation anesthesia machine (Model EM2 and halothane evaporator F-Model). Each compound (subjected to the test in the form of a sodium salt) was continuously intravenously injected into the tail vein in an amount of 0.4 ml/100 g to 0.6 ml/100 g at a rate of 0.05 ml per minute by a pump (Technicon AA II Proportioning Pump III, manufactured by Technicon Instruments Corporation) or rapidly intravenously injected. No injection was made to a control group. Gross pathological examination was conducted upon expiration of 6 hours after the ventrotomy in the case of the group to which the compound was administered. With respect to each of four lesions among pancreatic lesions i.e. petechia, ecchymosis, pancreatic necrosis and abdominal fatty necrosis, the grade and the distribution of lesions were scored with five grades of 0, 0.5, 1, 2 and 3 (severe lesions are 3). The sum of all lesions was designated as scores of pancreatitis lesions, and the sum of the score of petechia and the score of ecchymosis only was designated as scores of hemorrhagic lesions. The pancreatitis inhibition rate (%) and the hemorrhage inhibition rate (%) were obtained by the following formulas, and the results are shown in Table 13. ##EQU6##

H: Scores of pancreatitis lesions of the group to which a test compound was administered.

G: Scores of pancreatitis lesions of the control group. ##EQU7##

J: Scores of hemorrhagic lesions of the group to which a test compound was administered.

I: Scores of hemorrhagic lesions of the control group.

                  TABLE 13                                                         ______________________________________                                         Compound   Dose                                                                No.        (mg/kg)        *1     *2                                            ______________________________________                                          1         10             66     49                                             2          26*           46                                                    3         10             49     51                                             9         10             36     21                                            11          23*           52                                                   13          23*           100                                                  14          19*           52                                                   15         10             45     61                                            16          20*           52                                                   17          20*           73                                                   21          27*           57                                                   24          11*           68                                                   34         10             30     30                                            35         10             35     35                                            43          20*           81                                                   45          25*           62                                                   46          46*           36                                                   47          20*           68                                                   49          42*           68                                                   55          40*           65                                                   57          20*           60                                                   58         10             70     51                                            60         10             92     94                                            61         10             79     64                                            62         10             45     61                                            63         10             83     66                                            64         10             60     68                                            65         10             67     74                                            66         10             53     63                                            68         10             74     77                                            72         10             62     32                                            73         10             74     79                                            74         10             66     67                                            77         10             66     70                                            78         10             96     91                                            79         10             23     39                                            80         10             11      8                                            81         10             49     58                                            83         10             53     51                                            85         10             57     67                                            86         10             87     85                                            87         10             83     87                                            93         10             70     70                                            94         10             11     11                                            97         10             35     35                                            106        10             96     97                                            107        10             63     61                                            113        10             41     36                                            114        10             32     27                                            117        10             30     30                                            120         24*           100                                                  122        10             51     51                                            123        10             56     56                                            124        10             51     51                                            251        10             79     80                                            ______________________________________                                          Note:                                                                          Symbol * in the column for "Dose" indicates a case of continuous               intravenous injection, and no symbol indicates a case of single                intravenous injection.                                                         *1: Inhibition rate of hemorrhagic lesions (%)                                 *2: Inhibition rate of pancreatitis lesions (%)                          

To administer the compound of the present invention for the treatment of the above-mentioned diseases caused by phospholipase A₂, it is formulated alone or together with a pharmaceutically acceptable carrier into a drug composition suitable for peroral, or parenteral administration, such as a tablet, a powder, a capsule, a granule, an injection drug, an ointment, an inhalant or a suppository, and it is administered in the form of such a drug formulation.

As a drug formulation suitable for peroral administration, a solid composition such as a tablet, a capsule, a powder, a granule or a troach; or a liquid composition such as a syrup suspension, may be mentioned. The solid composition such as a tablet, a capsule, a powder, a granule or a troach may contain a binder such as fine crystalline cellulose, gum arabic, tragacanth gum, gelatine or polyvinyl chloride; an excipient such as starch, lactose or carboxymethyl cellulose; a disintegrator such as arginic acid, corn starch or carboxymethyl cellulose; a lubricant such as magnesium stearate, light silicic anhydride or colloidal silicon dioxide; a sweetener such as sucrose; or a flavoring agent such as peppermint or methyl salicylate. The liquid composition such as a syrup or a suspension may contain sorbitol, gelatine, methyl cellulose, carboxymethyl cellulose, a vegetable oil such as a peanut oil, an emulsifier such as lecithin as well as a sweetener, a preservative, a colorant or a flavoring agent, as the case requires. Such a composition may be provided in the form of a dried formulation. These formulations preferably contain from 1 to 95% by weight of the active compound.

A drug formulation suitable for parenteral administration may, for example, be an injection drug. The injection drug may be prepared by dissolving the compound in the form of a salt in usual water for injection, or may be formulated into a formulation suitable for injection such as a suspension or an emulsion (in a mixture with a pharmaceutically acceptable oil or liquid). In such a case, it may contain benzyl alcohol as an antibacterial agent, ascorbic acid as an antioxidant, a pharmaceutically acceptable buffer solution or a reagent for adjusting the osmotic pressure. Such an injection drug preferably contains from 0.1 to 8% by weight of the active compound.

A drug formulation suitable for topical or per rectal administration may, for example, be an inhalant, an ointment or a suppository. The inhalant may be formulated by dissolving the compound of the present invention alone or together with a pharmaceutically acceptable inert carrier in an aerosol or nebulizer solution, or may be administered to the resiratory airway in the form of fine powder for inhalation. In the case of fine powder for inhalation, the particle size is usually not more than 50 μm, preferably not more than 10 μm. Such an inhalant may be used, if neccesary, in combination with other antiasthematic agent or bronchodilator.

An ointment may be prepared by a conventional method by an addition of a commonly employed base or the like. The ointment preferably contains from 0.1 to 30% by weight of the active compound.

The suppository may contain a carrier for formulation which is well known in this field, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglyceride. The suppository preferably contains from 1 to 95% by weight of the active compound.

The above-mentioned drug compositions suitable for peroral, parenteral, topical or per rectal administration, may be formulated by conventional methods so that after administration to a patient, the active component will be rapidly discharged, gradually discharged or belatedly discharged.

The dose of the compound of the present invention varies depending upon the type of the compound, the administration method, the condition of the patient or the animal to be treated. The optimum dose and the number of administration under a specific condition must be determined by the judgement of a competent doctor. Usually, however, a daily dose to an adult is from about 0.01 g to about 10 g, preferably from about 0.05 g to about 5 g. In the case of the above inhalation method, the dose of the compound of the present invention is preferably from about 0.01 mg to about 100 mg per administration.

Now, specific Formulation Examples of the phospholipase A₂ inhibitor, the anti-inflammatory agent or the anti-pancreatitis agent of the present invention will be given.

    ______________________________________                                         FORMULATION EXAMPLE 1 (tablet)                                                 ______________________________________                                         (1)      Compound No. 30                                                                              200 mg                                                  (2)      Lactose       150 mg                                                  (3)      Starch         30 mg                                                  (4)      Magnesium stearate                                                                            6 mg                                                   ______________________________________                                    

The above composition is tabletted so that the components (1) to (4) constitute one tablet.

    ______________________________________                                         FORMULATION EXAMPLE 2 (powder or microgranule)                                 ______________________________________                                         (1)    Compound No. 35      200 mg                                             (2)    Sugar ester (DK ester F-160,                                                                        180 mg                                                    manufactured by Daiichi Kogyo)                                          (3)    Surfactant (Dekagreen 1-L,                                                                           15 mg                                                    manufactured by Nikko Chemicals)                                        (4)    Light silicic anhydride                                                                              25 mg                                             ______________________________________                                    

The component (1) is wet-pulverized in an aqueous solution containing 5% of the component (3). Then, 180 mg of the component (2) is added thereto, and the mixture is freeze-dried. The dried product is pulverized and mixed with the component (4).

The mixture is formed into a power or microgranule. Such a powder or microgranule may be sealed in a capsule to obtain a capsule drug.

    ______________________________________                                         FORMULATION EXAMPLE 3 (hard gelatine capsule)                                  ______________________________________                                         (1)    Sodium salt of Compound No. 10                                                                     250 mg                                              (2)    Starch              200 mg                                              (3)    Magnesium stearate   10 mg                                              ______________________________________                                    

The components (1) to (3) is packed in a hard gelatine capsule to obtain a hard gelatine capsule drug.

    ______________________________________                                         FORMULATION EXAMPLE 4 (injection drug)                                         ______________________________________                                         (1)    Sodium salt of Compound No. 19                                                                       1      g                                          (2)    Glucose               10     g                                          (3)    Distilled water for injection                                                                        200    ml                                         ______________________________________                                    

The components (1) to (3) are formulated into an injection drug in accordance with a usual method for preparation of an injection drug.

    ______________________________________                                         FORMULATION EXAMPLE 5                                                          (ointment for external skin application)                                       ______________________________________                                         (1)    Sodium salt of Compound                                                                              5      g                                                 No. 10                                                                  (2)    White vaseline        25     g                                          (3)    Stearyl alcohol       22     g                                          (4)    Propylene glycol      12     g                                          (5)    Sodium lauryl sulfate 1.5    g                                          (6)    Ethyl para-hydroxybenzoate                                                                           0.025  g                                          (7)    Propyl para-hydroxybenzoate                                                                          0.015  g                                          (8)    Purified water        100    g                                          ______________________________________                                    

The components (1) to (8) are formulated into an ointment for external skin application by a usual method for preparation of an ointment. 

We claim:
 1. A diaminotrifluoromethylpyridine derivative of the formula (I) or its salt: ##STR341## wherein X is --CW¹ R¹ and Y is --(NH)_(m) SO₂ R⁹ ; wherein W is an oxygen or sulfur atom, m is 0 or 1, and R¹ and R⁹ are the same or different and are alkyl, alkenyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, or a member selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl, adamantyl, noradamantyl, norbornanyl and norbornanonyl; wherein each of R¹ and R⁹ is optionally substituted with a member selected from the group consisting of a halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkylsubstituted amino, alkylsubstituted cyano and alkylsubstituted nitro.
 2. The diaminotrifluoromethylpyridine derivative or its salt according to claim 1, wherein R¹ is alkyl, haloalkyl, alkenyl, haloalkenyl, cycloalkyl, halogen-substituted cycloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl, or alkoxy- or haloalkoxy-substituted phenyl, and R⁹ is alkyl, haloalkyl, phenyl, halogen-substituted phenyl, alkyl- or haloalkyl-substituted phenyl or alkoxy- or haloalkoxy-substituted phenyl.
 3. The diaminotrifluoromethylpyridine derivative or its salt according to claim 1, wherein the diaminotrifluoromethylpyridine derivative is at least one derivative selected from the group consisting of N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyawcetamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-fluorobenzamide, N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene)carboxamide and N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide.
 4. The diaminotrifluoromethylpyridine derivative or its salt according to claim 1, wherein the diaminotrifluoromethylpyridine derivative is N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide
 5. A pharmaceutical composition for use as a phospholipase A₂ inhibitor, an anti-inflammatory agent or an anti-pancreatic agent which contains as an active ingredient said diaminotrifluoromethylpyridine derivative according to claim 1 and a carrier. 